The major objective of this renewal proposal for the Alzheimer's Disease Research Center (ADRC) at the University of Kentucky is to build on our broad, well balanced AD program. This program includes multidisciplinary basic and clinical research, exemplary clinical care, research training and strong outreach and education programs which are responsive to investigators, health care delivery professionals, community, state and region. The ADRC is complemented and strengthened by the presence of an AD Program Project-Grant. ADRC will continue to be the major programmatic activity of the Sanders-Brown Center on Aging. This ADRC proposal consists of: 1) An Administrative Core which will supervise and integrate all AD activities and assure appropriate data analyses, a Clinical Core which provides diagnostic services and thoroughly evaluated patients for clinical investigation and clinico-pathological correlative studies, a Neuropathology/Neurochemistry Core which provides well evaluated AD and control brains for investigators and an Information-Transfer Core which serves a strong outreach and educational function. 2) Four new research projects each with interesting preliminary data and each addressing key AD pathogenesis issues are proposed. Project #1 (Dr. Mattson) will study selective neuron death in relation to inter- and intracellular signaling mechanisms using protein chemistry and molecular biology tools. Project #2 (Dr. Sisken) addresses alterations in calcium regulation in fibroblast culture from familial AD. Project #3 (Dr.Sparks) will pursue, using clinical, morphological and neurochemical studies, interesting preliminary data that non-demented individuals with severe coronary artery disease have abundant cortical neuritic plaques. Project #4 will investigate impaired neural plasticity by accessing synaptic density and gene expression of neural cell adhesive molecules in AD. 3) Four pilot studies: Pilot #1 (Dr. McGillis) will study altered gene expression in AD utilizing subtractive cDNA cloning. Pilot #2 (Dr. Watt) will use photoaffinity probes to study altered GTP binding sites on tubulin in AD. Pilot #3 (Dr. Bhat) will evaluate the role of astrocytes in producing protein inhibitors of neural plasticity in AD. Pilot #4 (Dr. Zimmer) will study the potential transmissibility of AD utilizing ras oncogene, PrP and amyloid precursor protein expression as markers.